WO2001072727A1

WO2001072727A1 - Hair tonics

Info

Publication number: WO2001072727A1
Application number: PCT/JP2001/002349
Authority: WO
Inventors: Tokuro Iwabuchi; Hirotada Fukunishi; Koji Kobayashi; Masahiro Tajima
Original assignee: Shiseido Co., Ltd.
Priority date: 2000-03-27
Filing date: 2001-03-23
Publication date: 2001-10-04
Also published as: JP2001278873A

Abstract

Hair tonics excellent in hair-growing effects of preventing hair loss and growing new hair, which tonics contain as the active ingredient thiadiazolamide derivatives of the general formula (I) or salts thereof wherein R?1 and R2¿ are each H, lower alkyl, lower alkoxy, lower alkylamino, cyclic amino, lower alkylaminoalkyl, cyclic aminoalkyl, benzyloxy, or -O-R (wherein R is an unsaturated aliphatic hydrocarbon group); R3 is H, aryl, pyridyl, lower alkylamino, or cyclic amino; and A is a C¿1-5? divalent saturated hydrocarbon group.

Description

Description Hair restorer This application claims the priority of Japanese Patent Application No. 8666638, filed March 27, 2000, which is incorporated herein by reference. It is folded.

[Technical field]

The present invention relates to a hair restorer, a hair restorer containing a special amide derivative as an active ingredient.

[Background technology]

Conventionally, baldness and hair loss have been caused by activation of male hormones in hair roots, sebaceous glands, and other organs, decreased blood flow to hair follicles, excessive secretion of sebum, and the production of peroxide in the scalp. An abnormality is considered. For this reason, hair restoration agents (also referred to as hair restoration agents and hair growth promoters) that aim to promote hair growth and hair loss of the hair in the past have either eliminated the above-mentioned causes, or Compounds or compositions having a mitigating effect are generally incorporated.

For example, vitamins such as vitamin B and vitamin E, amino acids such as serine and methionine, vasodilators such as sempri extract and acetylcholine derivatives, anti-inflammatory agents such as purple root extract and hinokitiol, female hormones such as estradiol, Contains skin function enhancers such as cepharanthin.

However, despite the use of such agents, conventional hair restorers have not always had sufficient hair-growth effects such as prevention of hair loss and promotion of hair growth.

[Disclosure of the Invention]

An object of the present invention is to provide a hair restorer having an excellent hair restore effect such as prevention of hair loss and promotion of hair growth.

That is, the hair restorer according to the present invention comprises a thiadiazole represented by the following general formula (I). W

De derivatives or, characterized in that a pharmacologically acceptable salt thereof as an active ingredient ₍

(In the general formula (I), RR ² is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylamino group, a cyclic amino group, a lower alkylaminoalkyl group, a cyclic aminoalkyl group, a benzyloxy group, or It is a group represented by R (R is an unsaturated aliphatic hydrocarbon group).

R ³ is a hydrogen atom, an aryl group, a pyridyl group, a lower alkylamino group, or a cyclic amino group.

A is a divalent saturated hydrocarbon group having 1 to 5 carbon atoms. )

In the hair restorer of the present invention, R ¹ is preferably a hydrogen atom.

Further, it is preferable that R ² is a lower alkyl group.

Further, it is preferable that R ² is a lower alkoxy group.

Further, it is preferable that R ² is a lower alkylamino group.

Further, it is preferable that R ² is a cyclic aminoalkyl group.

Further, it is preferable that R ^{2 is} —O—R (R is an unsaturated aliphatic hydrocarbon group). Further, it is preferable that R ² is a hydrogen atom.

In the hair restorer of the present invention, R ¹ and R ² are preferably a lower alkyl group.

In the hair restorer of the present invention, R ^{1 is} preferably a benzyloxy group, and R ² is preferably a lower alkyl group.

In the hair restorer of the present invention, R ³ is preferably a lower alkylamino group or a cyclic amino group.

Further, it is preferable that R ³ is a hydrogen atom. In the hair restorer of the present invention, A is preferably an ethylene group or a propylene group.

The thiadiazole amide derivative according to the present invention is a compound represented by the following general formula (IA) or a salt thereof.

(In the general formula (ΙΛ), RR ² is a hydrogen atom or an alkyl group having 7 to 10 carbon atoms, but at least one of R ¹ R ² is not a hydrogen atom.

A is a divalent saturated hydrocarbon group having 1 to 5 carbon atoms. )

In the general formula (IA), A—R ³ is preferably — (CH ₂ ) ₂ —N (C ₂ H ₅ ) ₂ .

In the general formula (IA), R ¹ is preferably a hydrogen atom, and R ² is preferably an n-octyl group.

Further, the thiadiazolamide derivative according to the present invention is 2- (4-n-pentylbenzoyl) amino-5-getylaminoethylthio-1,3,4-thiadiazole or a salt thereof. Features.

In addition, the thiadiazolamide derivative according to the present invention is 2- (4-n-hexylbenzoyl) amino-5-decylaminoethylthio-1,3,4-thiadiazole or a salt thereof. Features.

In addition, the thiadiazole amide derivative according to the present invention is 2- (4-dimethylaminobenzoyl) amino-5-decylaminoethylthio-1,3,4-thiadiazole or a salt thereof. Features. In addition, the thiadiazole amide derivative according to the present invention is characterized in that it is 2- (dimethylaminobenzoyl) amino-5-decylaminoethylthio-1,3,4-thiadiazole or a salt thereof. I do.

Further, the thiadiazole amide derivative according to the present invention is 2- (3-piperidinomethylbenzoyl) amino-5- [3- (dimethylamino) propyl] thio-1,3,4-thiaziazole or a salt thereof. It is characterized by.

Further, the thiadiazole amide derivative according to the present invention is characterized in that it is 2_benzoylamino-5-diethylaminoethylthio-1,3,4-thiadiazole or a salt thereof.

[Best Mode for Carrying Out the Invention]

The lower alkyl group for R ¹ and R ² is a linear or branched alkyl group having 1 to 10 carbon atoms. For example, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl, Examples thereof include n-hexyl group, n-octyl group, n-nonyl group, and n-decyl group, and preferably n-octyl group. In the present invention, the definition of a lower alkyl group is the same as described above, unless otherwise specified.

The lower alkoxy group in R \ R ² means a hydroxyl group having a hydrogen atom replaced by a lower alkyl group, preferably a branched lower alkoxy group, particularly preferably an isopropoxy group or a tert-butoxy group. . In the present invention, the definition of lower alkoxy is the same unless otherwise specified.

R ^] and R ² can also be substituted amino groups such as lower alkylamino groups or cyclic amino groups. A lower alkylamino group is an amino group in which the hydrogen atom has been substituted by one or two identical or different lower alkyl groups. The cyclic amino group is a 4- to 8-membered saturated monocyclic amino group, and includes, for example, an azetidino group, a pyrrolidino group, a piperidino group and the like. Of the substituted amino groups in RR ^2, preferably a lower Al Kiruamino group, particularly preferably tert- Puchiruamino group, Jimechiruamino group. In the present invention, the definition of the lower alkylamino group and the definition of the cyclic amino group are the same unless otherwise specified. R ¹ R ² can also be an amino-substituted alkyl group such as a lower alkylaminoalkyl group or a cyclic aminoalkyl group. Of these, a cyclic aminoalkyl group is preferred, and a piperidinomethyl group is particularly preferred.

The benzyloxy group in R \ R ² is a group in which one or more substituents selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylamino group, a cyclic amino group, a nitro group and a cyano group are present on the benzene ring. You may have two. Among these substituents, preferred are halogen atoms, and particularly preferred is fluorine.

Further, R ¹ R ² can also be a group represented by _〇R. R means a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 20 carbon atoms containing at least one double bond, and is preferably a branched chain. As the branched unsaturated aliphatic hydrocarbon group, a prenyl group, a geranyl group, a neryl group, a phenylesyl group and the like are preferable, and a geranyl group is particularly preferable.

Of these, it is particularly preferred that R ¹ is a hydrogen atom and R ² is a hydrogen atom, a lower alkyl group or a cyclic aminoalkyl group.

R ³ can be a hydrogen atom, an aryl group such as a phenyl group or a naphthyl group, or a pyridyl group. The aryl group and the pyridyl group may have one or two substituents such as a lower alkyl group on the ring. For example, a trinole group, a xylyl group and the like can be mentioned. R ³ can also be a substituted amino group such as a lower alkylamino group or a cyclic amino group. The lower alkylamino group for R ³ is preferably a dimethylamino group, a getylamino group, or a diisopropylamino group, and particularly preferably a getylamino group. The cyclic amino group for R ³ is preferably a piperidino group. Among them, R ³ is preferably a lower alkylamino group or a cyclic amino group, and particularly preferably a lower alkylamino group.

Examples of the divalent saturated hydrocarbon group having 1 to 5 carbon atoms in A include a methylene group, an ethylene group, a propylene group, a 2-methylpropylene group, a butylene group, and a pentylene group. is there.

The thiadiazole amide derivative and a salt thereof according to the present invention can be produced by a known method. For example, a known amide such as a mixed acid anhydride method, an acid chloride method, a DCC method, a CDI method or an azide method is prepared from the following carboxylic acid (II) and substituted thiadiazole (III). The compound (I) of the present invention can be obtained by a bond formation reaction.

-A-I R 3

(II) Carboxylic acids (π) are commercially available or can be easily synthesized from benzoic acids having the corresponding functional groups. For example, a carboxylic acid (II) in which R ¹ or R ² is a lower alkoxy group, a lower alkylamino group, or one O—R is obtained by protecting a carboxyl group of a benzoic acid having a hydroxyl group or an amino group on a benzene ring. Alternatively, it can be obtained by introducing a lower alkyl group or a group R into the hydroxyl group or the amino group, and then deprotecting the carboxyl group protecting group. The introduction of the lower alkyl group or the group R is carried out by a reaction with a corresponding alcohol or alkene under acidic conditions, or a reaction with a corresponding alkyl halide or R—X (X is a halogen) under basic conditions. , It can be carried out.

Carboxylic acid (II) in which R ¹ or R ² is a lower alkylaminoalkyl group or a cyclic aminoalkyl group is obtained by protecting a carboxyl group of a benzoic acid having an alkyl group in a benzene ring, and then adding a halogen to the alkyl group. By substituting the halogen with a lower alkylamino group or a cyclic amino group under basic conditions, and then deprotecting the carboxyl group-protecting group. The introduction of the halogen can be carried out using プロ -promosuccinimide (NBS), クロロ -chlorosuccinimide (NCS) or the like. Carboxylic acid (II) in which R ¹ is a lower alkyl group and R ² is a benzyloxy group protects the carboxyl group of benzoic acid having a lower alkyl group and a hydroxyl group on a benzene ring, and then reacts with the corresponding benzyl group. It can be obtained by reacting with a halide under basic conditions to convert the hydroxyl group to a benzyloxy group and then deprotecting the carboxyl protecting group. The starting compound in this case is commercially available or can be synthesized by a known method. For example, benzoic acid having a hydroxyl group on the benzene ring After the carboxyl group is protected, the hydroxyl group is reacted with the corresponding alkenyl halide under basic conditions to convert the hydroxyl group to an alkenyloxy group. It can be obtained by performing it sequentially.

When R ¹ or R ² is a cyclic amino group, a known amide bond-forming reaction can be carried out from a benzoic acid having a halogen such as chlorine on the benzene ring as a substituent and a substituted thiadiazole (III). The desired compound of the present invention (I) can be obtained by forming a thiadiazole amide and then substituting the halogen with a cyclic amine. The substitution reaction of a halogen with a cyclic amine is usually carried out at 70 to 140 ° C in the absence of a solvent, and if necessary, a carbonated lime and copper chloride (II) or copper oxide (II) are added. Is also good.

On the other hand, substituted thiadiazoles (Ι Π) react, for example, with 2-amino-5-mercapto-1,3,4-thiadiazole and the corresponding halide X—A—R ³ under basic conditions. Can be obtained by

For the above synthesis method, the method described in Japanese Patent Application Laid-Open No. 9-149656 may be referred to.

The thiadiazole amide derivative which is an active ingredient of the hair restorer according to the present invention is exemplified below.

Compound 1:

2- (4-Isopropylbenzoyl) amino-5-decylaminoethylthio-1,3,4-thiazidazole

Compound 2:

2- (4-Isopropylbenzoyl) amino-5-disopropylaminoethylthio-1,3,4-

'~

Compound 3

2- (4-Isopropylbenzono-5-diisopropylaminoethylthio-1,3,4-no, ole hydrochloride

Compound 4

2— (4—tert-F, 'Tizole'-5-Getylaminoethylthio-1,3,4-thiadiazole

Compound 5

2- (4-tert-butylbenzoyl) amino-3- 5-sopropylaminoethylthio-1,3,4-thio Asiazole

Compound 6

2_ (4_ _n _pentylveil) amino-5-ethylethylaminothio-1,3,4-thiadiazole

Compound 7

2- (4-n-hexylbenzono- ₅ -ethylethylaminoethylthio-1,3,4-zole

Compound 8

2- (4-n- -5-ethyl-aminoethylthio-1,3,4-thiaasia Zol

Compound 9

2- (4-n-octylbenzyl) amino-5-getylaminoethylthio-1,3,4-thiadiazole

Compound 1 o

2- (3,5-di-tert-butylbenzoyl) amino-5-ethylethylaminoethylthio-1,3,4-thio

"-

Compound 1 1

2- (4-Isopropyloxy'yl) amino-5-ethylethylaminoethylthio-1,3,4- Thiadiazole

Compound 1 2

2- (4-tert-Butyloxybenzoyl) amino-5-methylethylaminothio-1,3,4-thio

-'Ichinore

Compound 1 3

2- (4-tert-butyla: zonyl) amino-5-ethylaminoethylthio-1,3,4-thiadiazole

Compound 1 4

2- (4-dimethylamidobenzoyl) amino-5-getylaminoethylthio-1,3,4-thia Jazol

Compound 1 5

2- (3-dimethylaminobenzyl) amino-5-ethylaminoethylthio-1,3,4-thia

-Ruhl

Compound 1 6

2- (4-geranyloxybenzylazozyl) amino-5-getylaminoethylthio-1,3,4-thiadiazole

Compound 1 7

2- (4-geranyloxybenzoinole) amino-5- [3- (ethylamino) propyl] thio-1,3 -Nore

Compound 1 8

2- (4-geranyloxybenol 5-[2— (piperethyl) thio-1,3,4-thiol

Compound 1 9

2- (4-geranyloxybenzoyl) amino-5- [3- (piperidino) propinole] thio-1,3,4-leur

Compound 20

2- (4-geranyloxybenzoyl) amino-5- (2-pyridyl) methylthio-1,3,4-thiazidazole

Compound 2 1

2- (4-geranyloxybenzoyl) amino-5-ethylthio 1,3,4--:

Compound 2 2

2- (4-geranyloxybenzoyl) ano-5-propylthio-1,3,4-thiadiazole

Compound 2 3

2- (4-geranyloxybenzoyl) amino-5-isobutylthio-1, 3,4-thiadiazole

Compound 24 2- (4-geranyloxybenzoyl) amino-5-benzylthio-1,3,4-thiadiazole

Compound 2 5

2- (3-piperi, methizolebenzo-5-ethyl-aminoethylthio-1,3,4-thiol

Compound 2 6

2- (3-H.peridinomethylbe: no-5- [3- (dimethylamino) propyl] thio-1,3,4-thiadiazole

Compound 2 7

2- [4- (4-Fluoroben-3-ino-5-Jethylaminoethylthio-1, 3,4-

Compound 2 8

2-[4- (4 Fluorobenzyloxy) -3-isobutylbamino-5-ethylethylaminoethylthio-1,3,4-thiadiazole hydrochloride

Compound 2 9

2-Benzoyla-5-Jetylamino etinorecho-1,3,4-thiadiazole

Although the mechanism of action of the thiadiazoamide derivative according to the present invention is not clear, it has an excellent hair growth promoting effect and an effect of extending the growth period of the hair cycle. Therefore, by applying this to the scalp, it is possible to treat, improve and prevent hair loss.

In addition, at least a part of the thiadiazolamide derivative according to the present invention can be prepared according to Japanese Patent Application Laid-Open No. 9-249496 (US Pat. No. 5,912,258). It is.

Hair restoration agents containing the thiadiazole amide derivative as an active ingredient include so-called androgenetic alopecia and androgenetic alopecia, light hair and alopecia as well as alopecia areata, pityriasis alopecia, and seborrheic alopecia. It can be applied to experimental alopecia. The amount of the thiadiazole amide derivative to be used should be appropriately determined according to gender, age, the degree of symptoms such as hair loss and light hair, etc., but is usually 0.01 to 50 mg / kg'd. , Preferably 0. 220 mg / kg. Apply or spray the scalp once or several times a day.

When the hair restorer according to the present invention is used as a drug, a quasi-drug, or a cosmetic, the dosage form can be arbitrarily selected as long as the effect of the present invention can be exerted. Examples include creams, gels, aerosols, and mousses. Specific examples include tonics, lotions, conditioners, scanolep treatments, shampoos and rinses.

In addition, in these preparations, in addition to the thiadiazolamide derivative according to the present invention, a component that can be generally added to a pharmaceutical or a cosmetic may be added in such an amount that the effects of the present invention are not impaired. it can. For example, as the medicinal component, as a drug having a blood circulation promoting action, there may be mentioned, for example, assembly extract, vitamin E and its derivatives, and nicotinic acid esters such as benzyl nicotinate. Drugs that promote blood circulation by local irritation include pepper tincture, tincture tincture, camphor, penilyl nonylate, and the like. Examples of the drug having a hair follicle activating action include hinokitiol, placentadex, photosensitizer, pantothenic acid and derivatives thereof. Examples of the drug having an antiandrogen action include hormonal drugs such as estradiol, ethelestradiol, and estrone. Iou Examples of drugs having antiseborrheic action, Chiokisoron include vitamin B _6, and the like.

Other examples include salicylic acid and resorcinol, which have a keratolytic and bactericidal action to prevent dandruff, and glycyrrhizic acid and its derivatives, glycyrrhetinic acid and its derivatives, and menthol to prevent scalp inflammation. Furthermore, amino acids such as serine, methionine, and arginine, vitamins such as biotin, herbal extracts, and the like are used for nutritional supplementation of hair follicles and activation of enzyme activity.

Also, Altea, Jouinin, Peppermint, Jouti, Pepper, Aloe, Ku Ko, Artemisia, Rice, Mankeishi, Mannenrou, Kosaiho, Enishida, Gentian, Tanjin, Hetima, Kikiyo, Pine, Kujin, Touki, Safflower, Barberry, Binguuji, Eucalyptus, Kagoso, Mokudzu, Goshi, Psycho, Kanzo, Kanzo Plant extracts such as hops, chrysanthemums, senega, sesame, sesame seeds, kash ゥ, katsukon, mai kai, saffron, rosemary, zio ゥ, zenioi can also be blended.

In addition, vasodilators such as alkoxycarbonylpyridine N-oxide, carpronium chloride, and acetylcholine derivatives; skin function enhancers such as cepharanthin; Antibacterial agents such as acid, trichlorocarbanide, bithino monozole, phenol, isopropinolemethi / lefeno monole; zinc and its derivatives; lactic acid or its alkyl ester; citric acid; succinic acid; organic acids such as malic acid; Protease inhibitors such as tranexamic acid and the like may be added. In addition, drugs such as cyclosporins, oxendrone, diazoxide, minoxidil and the like can be used.

Also, alcohols such as ethanol and isopropyl alcohol; polyhydric alcohols such as glycerin, propylene glycol and polyethylene dalicol; oils such as higher fatty acids, higher alcohols, hydrocarbon oils, natural oils and fats, ester oils, and silicone oils. Surfactants; fragrances; chelating agents; moisturizing agents such as 1,3-butylene glycol, hyal humic acid and its derivatives, maltitol, atelocollagen, sodium lactate; malmella mucilage, lipoxyvinyl polymer, xanthan gum Viscosity agents, etc .; High molecular compounds: Antioxidants: Ultraviolet absorbers; Dyes; Water; Stabilizers, and other components normally used in pharmaceuticals and cosmetics.

Hereinafter, the present invention will be described with reference to specific examples, but the present invention is not limited thereto.

Test Example 1 Hair growth promoting effect

(1) Test method

The hair growth test was performed using C3H I HeNCrj mice in the telogen phase of the hair cycle, using the method of Ogawa et al. (Normal and Abnormal Epidermal Differentiation ^ M. Seiji and IA Bernstein, 159 ~ 170 pages, 1982, University of Tokyo Press). That is, 10 mice per group, the back of each mouse was shaved by 3 x 4 cm with a norican, and 0.1 ml of ethanol (negative control) or ethanol solution of each test compound was added once a day. Applied. The hair growth effect of each test compound was measured 30 days after the start of application by measuring the area of the hair growth part on the back of the mouse and evaluating the ratio of the area of the hair growth part to the area of the shaved part as the hair regeneration area ratio (%). did.

(2) Result

Table 1 shows the average hair regeneration area ratio.

Test compound Compound concentration (w / v%) Hair regeneration area ratio (%)

No additive (negative control) 0

Compound 30.5 2 3

Compound 4 0.5 1 9

Compound 5 0 5 1 6

Compound 7 2 0 3 0

Compound 8 2 0 3 5

Compound 9 0 5 9 9

Compound 14 2 0 1 3

Compound 16 0 5 2 9

Compound 25 2 0 8 2

Compound 26 5 .0 7 0

Compound 29 — −2.098 As is clear from Table 1, the thiadiazolamide derivative according to the present invention has a hair growth promoting effect.

Among the above compounds, those which are not shown in Production Examples were prepared in accordance with Japanese Patent Application Laid-Open No. 9-246966 (US Pat. No. 5,912,258). Test Example 2 Growth period extension effect on hair cycle According to the method of hair growth drug test Hei 1 0 2 6 5 3 4 1 JP, _c the test method tested is brought into contact with the target substance to the hair follicle epithelial cultured cells in serum-free medium This is a method for determining whether or not the test compound has an effect of maintaining or prolonging the anagen phase in the hair cycle, based on the degree of cell proliferation at the time of the growth. In this test example, cultured follicular epithelial cells of rat body hair obtained by the method described in Japanese Patent Application Laid-Open No. 10-265341 were used.

(1) Hair follicle epithelial cell culture medium

From the number of viable cells was calculated in blood count plate, so that the final concentration in the rat hair follicle epithelial cultured cells becomes ^{5. 0 X 1 0 4 ce 1} 1 / m 1, KGM medium (epidermal keratinocytes basal medium) To obtain a cultured cell suspension. The KGM medium was prepared by adding pituitary pituitary extract (final concentration: 0.4 vol%), insulin (final concentration: 0.5 μgZm1) to KBM medium (modified MCDB medium: Kronetics). ), Medium containing cortisone (final concentration: 0.5 μg, ml) and h-EGF (Epidermal Growth Factor, final concentration: 0.1 ng / m 1).

Cultured cell suspension 9 6 we 1 1 plate: seeded at a rate of 0. 2 ml / well (1 0 X 1 0 4 ce 1 1 / we 1 1.) To (I collagen coated plates Fuarukon Co.) did. After the cells were left at room temperature for about 20 minutes until they settled to the bottom of we11, the cells were cultured at 37 ° C and 5% CO ₂ for one day to prepare a culture medium supplemented with hair follicle epithelial cells.

(2) Test medium

(a) Target substance-containing medium: The target substance was dissolved in DMSO and added to KBM medium to a final concentration of 1.0 X 1 CT ⁷ M (DMS O concentration 0.1%).

(b) Negative control: only DMSO was added to KBM medium (DMSO concentration 0.1%)

(c) Positive control: KGM medium was used.

(d) KBM medium

(3) Medium exchange and Atsushi

Remove the aspirator from the KGM medium in the 96 we11 plate obtained in (1) above, taking care not to damage the cells attached to the bottom of we11, and then immediately proceed to (2) Medium from both ends of we11 at a rate of 0.2 ml / we11. And the medium was exchanged.

37 ° C, 5% C0 ₂ at 20 between After culturing performs Alama one Bull one Atsusi, the absorbance was measured at 5 95 nm and 570 nm using a microplate reader (BIO manufactured RAD), each for negative control The degree of cell proliferation (%) of the medium was calculated. From each cell proliferation degree (I), a cell proliferation index was calculated according to the following formula. Cell growth promotion index =

[(Target medium supplemented medium I) one (KBM medium 1)] / [(e. "Tif" control P-I) one (KBM medium 1)] At this time, the cell growth promotion index of KBM medium is 0, The cell growth promotion index of the positive control is 1. The pituitary pituitary extract, h-EGF, in the positive control is a substance that is known to affect the proliferation of hair follicle epithelial cells in culture.

Table 2 shows the results.

Table 2 Target substances Cell growth promotion index (mean soil S.D.)

Compound 1 • 7 ± 0.5 *

Compound 3.4 ± 0.4 *

Compound 4.2 ± 0.3 *

Compound 5 • 8 ± 0.5 *

Compound 6.7 ± 0.2 *

Compound 7.5 ± 0.5 *

Compound 8.9 ± 0.2 *

Compound 9.8 ± 0.2 *

Compound 10.8 ± 0.4 *

Compound 11 • 0 ± 0.5 *

Compound 12.8 ± 0.3 *

Compound 13.7 ± 0.5 *

Compound 15.5 ± 0.1 *

Compound 16.7 ± 0.5 * Compound 18 1.6 ± 0.5 *

Compound 21 1.5 ± 0.5 *

Compound 25 2.8 ± 0.4 *

Compound 26 2.1 ± 0.3 *

Compound 28 2.0 ± 0.4 *

DMS0 (Ne power, 'Tif, Control P-rule) 0.2 ± 0.4

* Significant difference P <0.0 As shown in Table 2, the thiadiazole amide derivative according to the present invention exhibited a growth activity of hair follicle epithelial cell culture. This suggests that these derivatives have an action of maintaining or prolonging the anagen phase of the hair cycle by maintaining the mitotic proliferation activity of hair follicle epithelial cells.

Among the above compounds, those not shown in the Production Examples were prepared according to Japanese Patent Application Laid-Open No. 9-249666 (US Pat. No. 5,912,258). Production Example 1

2- (4-n-hexylbenzoyl) amino-5-getylaminoethylthio-1,3,4-thiadiazole (compound 7)

2-Amino-5-oxygenate chill § amino ethyl thio - 1, 3, 4 - the chloroform solution 15ml thiadiazole 1.50 g, added Toryechiruamin 0. ⁹ 9 ml, then under ice-cooling, hexyl benzoyl to 4-n- The mixture was added with 1.42 ml of mouth-opening and stirred at room temperature for 19 hours. The reaction solution was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, mouth form: methanol = 30: 1) to give 2.33 g of the title compound as a pale yellow solid.

Awakening: _{R (CDC1 3) δ 8.07 (} 2Η, d, J = 8.4Hz), 7.34 (2H, d, J = 8.4Hz), 3.38 (2H, t, J = 6.8Hz), 2.84 (2H, t, J = 6.8Hz), 2.69 (2H, t, J = 7.6Hz), 2.56 (4H, q, J = 7.2Hz), 1.65 (2H, quintet, J = 7.6Hz), 1.40-1.24 (6H, m), 1.02 (6H, t, J = 7, 2Hz), 0.89 (3H, t, J = 6.8Hz).

Production Example 2

2- (4-n-heptylbenzoyl) amino-5-getylaminoethylthio-1,3,4-thiazi Fazole (Compound 8)

2-amino-5-ethylethylethinorethio-1,3,4-thiadiazol 1.40 g of chloroform solution in 14 ml of triethylamine 0.93 ml was added, and then 4-n- 1.44 ml of heptyl benzoylc mouth light was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, mouth form: methanol = 50: 1 to 30: 1) to obtain 2.26 g of the title compound as a pale yellow solid.

Ή-NMR (CDC1 :,) δ: 8.09 (211, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 3.38 (2H, t, J = 7.2 Hz),

2.84 (2 to 1, t, J = 7.2 Hz), 2.69 (2H, t, J = 7.6 Hz), 2.56 (4H, q, J = 7.2 Hz), 1.65 (2H, quintet, J = 7.6Hz), 1.0-1.24 (8H, m), 1.01 (6H, t, J = 7.2Hz), 0.88 (3H, t, J = (6.8 Hz).

Production Example 3

2- (4-dimethylaminobenzoyl) amino-5-getylaminoethylthio-1,3,4-thiadiazole (compound 14)

To 1.20 g of 4-dimethylaminobenzoic acid was added 12 ml of chloroform and 1.01 ml of triethylamine. Then, under ice-cooling, 0.64 ml of thioyrc mouth was added, followed by stirring for 30 minutes. After concentrating the reaction solution, 16 ml of chloroform and 1.69 g of 2-amino-5-ethylaminoethylthio-1,3,4-thiaziazole were added to the residue, and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform: methanol = 30: 1 to 10: 1) to give 2.27 g of the title compound as a pale yellow solid.

Ή-NMR (CDC1.,) Δ: 8.00 (2Η, d, J = 8.8 Hz), 6.72 (2H, d, J = 8.8 Hz), 3.37 (2H, t, J = 7.2 Hz),

3.08 (6H, s), 2.84 (2H, t, J = 7.2Hz), 2.56 (4H, q, J = 7.2Hz), 1.01 (6H, t, J = 7 2 Hz).

Production Example 4

2- (3-Dimethylaminobenzoyl) amino-5-getylaminoethylthio-1,3,4-thiadiazol (compound 15)

To 1.20 g of 3-dimethylaminobenzoic acid was added 12 ml of chloroform and 1,01 ml of triethylamine, and then 0.64 ml of thionyl chloride was added under ice-cooling, followed by stirring for 30 minutes. After concentrating the reaction mixture, the residue was diluted with 10 ml of chloroform and 2-amino-5-ethylaminoethylthio-1,3,4-

1.69 g / l was added and stirred at room temperature for 3 hours. The reaction solution was saturated with aqueous sodium bicarbonate and saturated The extract was washed successively with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform: methanol = 30: 1 to 10: 1) to give 2.38 g of the title compound as a pale yellow solid.

_{'H- MR (CDC1 3) δ} : 7.37 (2H, m), 7.33 (1H, m), 6.94 (1H, m), 3.36 (2H, t, J = 7.3Hz), 3.01 (6 H, s) , 2.83 (2H, t, J = 7.3Hz), 2.56 (4H, q, J = 7.2Hz), 1.02 (6H, t, J = 7.2Hz).

Production Example 5

2- (3-piridinomethylbenzoinole) amino-5- [3- (dimethylamino) propyl. Ru] thio-1,3,4-thiadiazole (compound 26)

8.00 g of 2-amino-5-mercapto-1,3,4-thiadiazole, 9.50 g of 3-dimethylaminopropyl chloride hydrochloride and 6.74 ₈ of potassium hydroxide in methanol 150! 111 for 16 hours at room temperature After stirring, the mixture was stirred at 40 ° C for 4 hours, and further stirred at 70 ° C for 5 hours. After the reaction solution was concentrated under reduced pressure, an aqueous solution of potassium hydroxide was added, extracted with ethyl acetate, and washed with saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain 10, 40 _g of 2-amino-5- [3- (dimethylamino) propyl] thio-1,3,4-thiadiazole as a white solid.

16 ml of chloroform and 0.88 ml of triethylamine were added to 1.60 g of 3-piperidinomethylbenzoic acid, and then 0.55 ml of thionyl chloride was added under ice-cooling, followed by stirring for 30 minutes. After concentrating the reaction mixture, add 1 _ml 37 _g of 2-amino-5- [3- (dimethylamino) propyl] thio-1,3,4-thiadiazol to the residue and add 8 ml of chloroform in the residue. We stirred. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained solid was recrystallized (n-hexane-ethanol) to give 1.74 g of the title compound as a pale yellow solid.

Awake R (CDCl ^) δ: 8.02 (2Η, m), 7.61 (1H, d, J = 8.OHz), 7.48 (1H, t, .1 = 8.0Hz), 3.55 (2H, s), 3.28 ( 2H, t, J = 7.2Hz), 2.40 (6H, t, J = 7.2Hz), 2.22 (6H, s), 1.92 (211, quintet, J = 7.2Hz), 1.57 (4H, m), 1 .4 (2H, m).

Production Example 6

2-benzoylamino-5-ethylaminoethylthio-1,3,4-thiadiazole (compound 29)

1.32 ml of triethylamine was added to 20 ml of a chloroform solution of 2.00 g of 2-amino-3,3-ethylethylaminothio-1,3,4-thiaziazole, and then cooled on ice. After adding 1.00 ml of a mouth light and stirring for 3 hours, the mixture was stirred at room temperature for 19.5 hours. The reaction solution was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel gel chromatography (silica gel 75 g, black form: methanol 3

0: 1 to 10: 1 by) to yield the title compound 2. ⁷ 3 g of a pale yellow solid.

! H—NMR (CDCl _{: i} ) δ: 8.19 (2H, d, J = 8.0 Hz), 7.63 (1H, t, J = 8.0 Hz), 7.54 (2H, t, J = 8.0 Hz),

3.37 (2H, t, J = 7.2Hz), 2.83 (2H ₍ t, J = 7.2Hz), 2.55 (4H, q, J = 7.2Hz), 1.01 (6H , T, J = 7.2Hz).

Production example Ί

2- (4-n-pentylbenzoyl) amino-5-ethylenaminoethylthio-1,3,4-thiazidazole (compound 6)

0.6 g of sodium hydride and 2.32 g of 2-amino-5-ethylethylthio-1,3,4-thiazidazole were stirred in 30 ml of tetrahydrofuran under ice-cooling; for 30 minutes. Separately, 1.92 g of 4 n-pentylbenzoic acid and 1.78 _g of carboerdiimidazole were stirred in 30 ml of tetrahydrofuran at room temperature for 30 minutes. This was added to the previous reaction solution and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol-2-10: 1). The obtained solid was recrystallized from n-hexane to give 2.97 g of the title compound as a white solid.

^{_{! H-NMR (CDC1 3)}} δ: 8. 15 (. 2Η, d, J = 8 3Hz), 7. 33 (. 2H, d, J = 8 3Hz), 3. 38 (2H, t, J = 6.8 Hz), 2.83 (2H, t, J = 6.8 Hz), 2.68 (2H, t, J = 7.3 Hz), 2.55 (4H, q, J = 6.8 Hz), 1.60-1, 71 (2H, m), 1.00 (6H, t, J = 7.3Hz), 0.90 (3H, t, J = 6.8Hz).

Production Example 8

2- (4-n-octylpenzinole) amino-5-decylaminoethylthio-1,3,4-thiadiazole (compound 9)

And sodium arsenate Dori de 0. 6 g, 2-amino - 5 - Jefferies chill aminoethylthio - 1, 3, 4 - and thia Jiazoru 2. 32 g, in as tetrahydrofuran ³ 0 ml, and stirred for 30 minutes under ice-cooling . Separately, 2.34 g of 4-n-octylbenzoic acid and 1.78 g of carboerdiimidazole were stirred in 30 ml of tetrahydrofuran under ice-cooling for 30 minutes. This was added to the previous reaction solution and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with black hole form. Anhydrous sodium sulfate After drying with a pam, it was concentrated under reduced pressure. The residue was purified by gel chromatography on silica gel (form: methanol = 10: 1). The obtained solid was recrystallized from n-hexane to give 2.82 g of the title compound as a white solid.

Ή-NMR (CDC1 ₃ ) 6: 8.14 (2Η, d, J = 8.3 Hz), 7.30 (2H, d, J = 8.3 Hz), 3.40 (2H, t, J = 7.3 Hz), 2.86 (2H, t , J = 7.3Hz), 2.68 (2H, t, J = 6.8Hz), 2.58 (4H, q, J = 6.8Hz), 1.72-1.58 (211, m),

1.38-1.19 (10H, m), 1.02 (611, t, .1 = 6.8Hz), 0.88 (3H, t, J = 6.8Hz).

Production Example 9

2- [4- (4-Fluorobenzyloxy) -3-isobutylbenzoyl] amino-5-ethylethylaminoethylthio-1,3,4-thiadiazol hydrochloride (Compound 28)

Is 2.00 g of 2- [4- (4-fluorobenzyloxy) -3-isobutylbenzoyl] amino-5-decylaminoethylthio-1,3,4-thiadiazole dissolved in 50 ml of methanol? Then, 10 ml of methanol containing 10% hydrochloric acid was added, and the mixture was stirred at room temperature for 10 minutes. This was concentrated under reduced pressure to obtain 2.10 g of the title compound as a white solid.

_{^ -NMR (CDC1 3) δ:} 12.47 (IH, S), 8.06 (IH, d, J = 8.8Hz), 7.91 (IH, S), 7.40 (2H, d, J = 8.8 Hz), 7.09 (2H , t, J = 8.3Hz), 7.01 (1H, d, J = 8.3Hz), 3.90-3.86 (2H, m), 3 remaining 0.52-3.46 (2H, m), 3.

Mouth

35-3.13 (4H, m), 2.59 (2H, d, J = 6.8 Hz), 1.87-2.05 (IH, m), 1.1 (6H, t, J = 7.3 Hz), 0, 91 (6 H , d, J = 6.4Hz).

Formulation Example 1 Lotion

95% Ethanore 50.0% by weight ° /.

Glycyrrhizinate monoammonium 0.1

Compound 1 4.0

Sodium lauryl sulfate 0.1

POE (40) hydrogenated castor oil 0.5

Succinic acid qs

Spice

Pigment

purified water

(Formulation method)

Dissolve POE (40) hydrogenated castor oil and fragrance in 95% ethanol, then add purified water. After the addition, the other components were added and dissolved by stirring to obtain a clear liquid lotion.

Formulation Example 2 Lotion

95% Etano one Honoré 90.0 wt ^_0/0 Vitamin E Asete Ichito 0.05

Compound 25 5.0

Sodium lauryl sulfate 0.06

Propylene Dariko 0.1

POE (40) hydrogenated castor oil 0.5

Lactic acid

Sodium lactate qs

Appropriate amount of fragrance

Dye amount

Purified water balance

(Formulation method)

POE (40) hydrogenated castor oil and flavor were dissolved in 95% ethanol, purified water was added, and then other components were added, followed by stirring and dissolution to obtain a transparent liquid lotion.

Formulation Example 3 Hair Tonic

Compound 25 5.0 weight. /.

Hinoki Chino 1.0

Vitamin B 6 0.2

Vitamin E acetate 0.02

Menthol 0.2

Assembly extract 1.0

Salicylic acid 0.1

Propylene glycol 2.0

POE (10) Monostearate 2.0

75% ethanol residue

(Formulation method)

Each component was sequentially added to 75% ethanol, and stirred to dissolve to obtain a hair tonic. Formulation Example 4 Hair tonic

Compound 1 14.0% by weight Hinokitiol 1.0

Vitamin B 6 0.2

Vitamin E 0.02

Mento / Re 0.2

Salicylic acid 0.1

Propylene Dali Cornole 2.0

Sodium hyaluronate 0.0 1

POE (10) Monostearate 2.0

70% ethanol remaining

(Formulation method)

Each component was sequentially added to 70% ethanol, and dissolved by stirring to obtain -A tonic Formulation Example 5 OZW emulsion

Phase A:

POE (60) hydrogenated castor oil 2.0 weight. / ₀ glycerin 1 0.0

Dipropylene glycol 10.0

1,3-butylene glycol 4.0

Compound 3 3.0

Polyethylene glycol 1 500 5.0

Phase B:

Isosecetyl octanoate 1 0.0

5.0 Vaseline 2.0

Propi / Reno ヽ. Raven 2.0

Phase C:

Carboxyvinyl polymer 1% aqueous solution 30.0

Hexametaphosphate sodium 0.03 Deionized water 8.35

D phase:

Ion exchange water 4.5

E phase:

KOH 0.1 2

Ion exchange water residue

(Formulation method)

The phases A and B were each heated and dissolved at 60 ° C., mixed, and treated with a homomixer to prepare a gel. Phase D was gradually added to this gel and dispersed with a homomixer.

Next, the previously dissolved phase C was added to the gel dispersion, and the previously dissolved phase E was added, and emulsified with a homomixer to obtain a ZW type emulsion.

Formulation Example 6 Cream

Phase A:

Dimethylhexyl POE (5) Aminoxide 2.5 weight. /. Liquid paraffin 5.0

Setostearyl Lanorecol 5.5

Glyceryl monostearate 3.0

P〇E (20) 2-octyldodecyl ether 3 · 0

H. Mouth hi. Noreno Raven 0.3

Fragrance 0.1

Phase B:

Compound 4 3.0

Glycerin 8.0

Dipropylene dalicol 20.0

Polyethylene glyco 4000

Hexametaphosphate sodium 0.005

Ion exchange water residue

(Formulation method)

Heat and dissolve phase A and phase B respectively, mix and emulsify with a homomixer and cream I got

Formulation Example 7

Stock formulation:

95% ethanol 50.0% by weight glycyrrhetinic acid 0.1

Compound 53.0

Assembly extract 0.1

Sodium lauryl sulfate 0.1

POE (40) hydrogenated castor oil 0.5

Lactic acid

Suitable for sodium lactate M

Appropriate amount of fragrance

Ion exchange water residue

Filling formula:

Stock solution 50.0

Liquefied petroleum gas 50.0

(Formulation method)

An undiluted solution was prepared by mixing and dissolving the ingredients of the undiluted solution, filled in a can, fitted with a valve, and filled with gas to obtain an aerosol spray.

Formulation Example 8 Shampoo

(1) Cocoyl methyl taurine sodium 2.0% by weight

(2) POE (8) oleyl ether 2.0

(3) Jetanolamide laurate 4.0

(4) Ethylene glycol fatty acid ester 1.0

(5) Glycerin 0.2

(6) Menthol 0.1

(7) Compound 10 2.0

(8) Disodium edetate 0.1

(9) Appropriate amount of fragrance (10) Purified water balance

(Formulation method)

The purified water was heated to 70 ° C., and the components (1) and (9) were sequentially added, mixed by stirring and dissolved, and cooled to obtain a shampoo.

Formulation Example 9 Rinse

(1) Stearyl trimethylammonium chloride 1.5% by weight

(2) Dimethylpolysiloxane (20 cs) 3.0

(3) POE (10) oleyl ether 1.0

(4) Glycerin 5.0

(5) Compound 1 1 2.5

(6) 4-tert-butyl-4'-methoxybenzoylmethane

(7) UV absorber

(8) Remaining purified water

(Formulation method)

(1), (3), and (4) were added to the purified water, and the mixture was heated to 70 ° C. to obtain an aqueous phase. The other components were heated and melted and heated to 70 ° C to obtain an oil phase. The oil phase was added to the aqueous phase, mixed by stirring with an emulsifier, and cooled to obtain a rinse.

Formulation Example 10 Scalp treatment

Stock formulation:

(1) Liquid paraffin 27.0

(2) Stearic acid 5.0

(3) Cetanol 5.0

2.0

(5) POE Sorbitan Monoolee 3.0

(6) Compound 1 2 3.0

(7) 1,3-butylene glycol 5.0

(8) Preservatives a

(9) Purified water balance

Filling formula: Stock solution 50.0

Liquefied petroleum gas 50.0

(Formulation method)

Dissolve components (5) to (6) in components (1) to (4), heat to 80 ° C, dissolve uniformly, cool to 30 ° C, and convert this to 30 ° C ( 7) to (9) were mixed and stirred to produce a stock solution. The stock solution was filled in a can with a propellant to obtain a scalp treatment. Formulation Example 1 1 Scalp treatment

Stock formulation:

(1) Hinokitiol 0.1% by weight

(2) Assembly extract 1.0

(3) Vitamin B 6 0.1

(4) Vitamin E 0.0 1

(5) Menthol 0.1

(6) Salicylic acid 0.001

(7) Compound 1 3 2.5

(8) POE sorbitan monolayer 0.1

(9) full ¹¹ b propylene glycol 2.0

(10) 75% ethanol residue

Filling formula:

Stock solution 50.0

Dimethyl ether 50.0

(Formulation method)

A scalp treatment was obtained in the same manner as in Preparation Example 10.

Formulation example 1 2 Hair tonic

Compound 1 6 4.0% by weight

Hinokichiru 0.05

Vitamin B 6 0.2

Vitamin E 0.02

Menthol 1.0 Propylene glycol 2.0

Sodium hyaluronate 0.0 1

P〇E (10) Monostearate 2.0

70% ethanol residue

(Formulation method)

Each component is added to 70% ethanol sequentially and stirred to dissolve.

Compound 1 8 3.0% by weight

Vitamin B 6 0.2

Vitamin E 0.02

Menthol 0.2

Salicylic acid 0.1

Propylene Glyco 2.0

Sodium hyaluronate 0.0 1

POE (10) Monostearate 2.0

70% ethanol residue

(Formulation method)

Each component was sequentially added to 70% ethanol and stirred to dissolve to obtain a hair tonic: Formulation Example 14 Hair tonic

Compound 21 2.0% by weight

Hinokitiol 1.0

Vitamin E 0.02

Menthol 0.2

Salicylic acid 0.2

H. Propylene glycol 2.0

Sodium hyaluronate 0.05

POE (10) Monostearate 2.0

70% ethanol residue

(Formulation method) Each component was sequentially added to 70% ethanol, stirred and dissolved to obtain a hair tonic. Formulation Example 1 5 Hair tonic

Compound 7 2.5% by weight

Hinokitiol 1.2

Vitamin E 0.02

Menthol 0.2

Salicylic acid 0.1 5

Propylene glycol 3.0

Sodium hyaluronate 0.02

POE (10) Monostearate 2.0

70% ethanol remaining

(Formulation method)

Each component was sequentially added to 70% ethanol, and dissolved by stirring to obtain a hair tonic. Formulation Example 1 6 Hair tonic

Compound 8 3.5% by weight

Hinokitiol 1.0

Vitamin B 6 0.2

Vitamin E 0.02

Men Tonore 0.8

Salicinoleic acid 0.2

Propylene Glycosole 2.5

Sodium hyaluronate 0.0 1

POE (10) Monostearate 2.0

70% ethanol residue

(Formulation method)

Each component was sequentially added to 70% ethanol, stirred and dissolved to obtain a hair tonic. Formulation Example 1 7 Hair tonic

Compound 1 5 4.0 weight. /.

Hinokitiol 1.2 Vitamin B 6 0.5

Vitamin E 0.03

Menthol 0.5

Acid 0.1

Propylene dalycol 2.0

POE (10) Monostearate 2.0

70 Ethanol residue

(Formulation method)

Each component was added sequentially to 70% ethanol, and the mixture was stirred and dissolved to obtain a hair tonic. _C Preparation example 18 Hair tonic

Compound 26 2.5 weight. /.

Vitamin B 6 0.2

Vitamin E 0.02

Menthol 0.2

Salicylic acid 0.1

Propylene dalicol 4.0

Sodium hyaluronate 0.0 1

POE (IO) Monostearate 2.0

70% ethanol residue

(Formulation method)

Each component was added sequentially to 70% ethanol, and stirred to dissolve, resulting in a hair tonic Formulation Example 19 Hair tonic

Compound 28 2.5 weight. /.

Vitamin E 0.02

Menthol 0.5

Propylene dalicol 3.0

Sodium hyaluronate 0.01

POE (10) Monostearate 2.0

70% ethanol residue (Formulation method)

Add each component to 70% ethanol sequentially and stir and dissolve to obtain a hair tonic _c formulation example 20 Hair tonic

Compound 9 4.0% by weight

Hinokitiol 0.05

Vitamin E 0.02

Menthol 0.5

Salicylic acid 0.1

Propylene dalicol 2.5

Sodium hyaluronate 0.0 1

POE (IO) Monostearate 2.0

70% ethanol residue

(Formulation method)

Each component was sequentially added to 70% of the gel, and dissolved by stirring to obtain hair and tonic. Formulation Example 21, Artnic

Compound 6 2.0% by weight

Vitamin E 0.01

Men Tonore 0.5

Propylene glycol 2.0

POE (10) Monostearettle 2.0

70% Ethanore Remaining

(Formulation method)

Sequentially adding the components in a 70% Etano Ichiru, and dissolved by stirring, tonic to _c present invention to obtain a hair tonic, by the active ingredient and to Rukoto certain thiadiazole Ami de derivative or a salt thereof, originating It can exert a hair-promoting effect and an effect of prolonging the anagen phase during the hair cycle, and is very effective in preventing and treating hair loss.

Claims

The scope of the claims

1. A hair restorer comprising, as an active ingredient, a thiadiazole amide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

(In the general formula (I), RR ² is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylamino group, a cyclic amino group, a lower alkylaminoalkyl group, a cyclic aminoalkyl group, a benzyloxy group, or —O— It is a group represented by R (R is an unsaturated aliphatic hydrocarbon group).

A is a divalent saturated hydrocarbon group having 1 to 5 carbon atoms. )

2. The hair restorer according to claim 1, wherein R ¹ is a hydrogen atom.

3. The hair restorer according to claim 2, wherein R ² is a lower alkyl group.

4. In hair tonic according to claim 2, hair tonics, wherein R ² is a lower alkoxy group.

5. In hair tonic according to claim 2, baldness remedy to feature that R ² is a lower alkyl amino group.

6. In hair tonic according to claim 2, baldness remedy to feature that R ² is a cyclic amino group.

7. In hair tonic according to claim 2, characterized in that 1¾ ² gar 0- 1¾ (R is an unsaturated aliphatic hydrocarbon group) baldness remedy.

8. The hair restorer according to claim 2, wherein R ² is a hydrogen atom.

9. The hair restorer according to claim 1, wherein R ¹ and R ² are lower alkyl groups.

10. The hair restorer according to claim 1, wherein R ¹ is a benzyloxy group and R ² is a lower alkyl group.

1 1. The hair restorer according to claim 1, wherein R ³ is a lower alkylamino group or a cyclic amino group.

1 2. The hair restorer according to claim 1, wherein R ³ is a hydrogen atom.

1 3. The hair restorer according to claim 1, wherein A is an ethylene group or a propylene group.

14. A thiadiazole amide derivative represented by the following general formula (II) or a salt thereof.

(In the general formula (IA), RR ² is a hydrogen atom or an alkyl group having 7 to 10 carbon atoms, but at least one of R ¹ R ² is not a hydrogen atom.

A is a divalent saturated hydrocarbon group having 1 to 5 carbon atoms. )

15. The thiadiazole amide derivative or a salt thereof according to claim 14, wherein one A—R ^{3 is} — (CH ₂ ) ₂ —N (C ₂ H ₅ ) ₂ .

1 6. The compound according to claim 14 or 15, wherein R ¹ is a hydrogen atom, and R ² A thiadiazoamide derivative or a salt thereof, which is an octyl group.

17.2- (4-n-pentylbenzoyl) amino-5-ethylaminoethylthio-1,3,4-thiadiazole or a salt thereof.

18.2- (4-n-Hexylbenzoyl) amino-5-ethylaminoethylthio-1,3,4-thiadiazol or a salt thereof.

19.2. 2- (4-Dimethylaminobenzoyl) amino-5-getylaminoethylthio-1,3,3,4-thiaziazole or a salt thereof.

20.2- (3-Dimethylaminobenzoyl) amino-5-ethylaminoethylthio-1,3,4-thiadiazol or a salt thereof.

21.2- (3-Piperidinomethylbenzoyl) amino-5- [3- (dimethylamino) propyl] thio-1,3,4-thiadiazol or a salt thereof.

22. 2-Benzoylamino-5-ethylaminoethylthio-1,3,4-thiadiazol or a salt thereof.